Condition Description

Hereditary
leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant condition
characterized by cutaneous leiomyomata, uterine leiomyomata (fibroids), and/or
a single renal tumor. The majority (three-quarters) of individuals with HLRCC
present with a single or multiple cutaneous leiomyoma. Cutaneous leiomyomata
appear as skin-colored to light brown papules or nodules distributed over the
trunk and extremities and occasionally on the face and appear at a mean age of
25 years, increasing in size and number with age. Uterine leiomyomata are
present in almost all females with HLRCC and tend to be numerous and large; age
at diagnosis ranges from 18 to 52 years, with most women experiencing irregular
or heavy menstruation and pelvic pain. The presence of cutaneous leiomyomata
correlates with the presence of uterine fibroids in females. Renal tumors
causing hematuria, lower back pain, and a palpable mass are usually unilateral,
solitary, and aggressive and range from type 2 papillary to tubulo-papillary to
collecting-duct carcinomas. They occur in about 10%-16% of individuals with
HLRCC; the median age of detection is 44 years. Disease severity shows
significant intra- and interfamilial variation.

HLRCC is
diagnosed by the presence of multiple cutaneous leiomyomas with at least one
histologically confirmed leiomyoma or by a single leiomyoma in the presence of
a positive family history of HLRCC. Diagnosis is confirmed by testing of
fumarate hydratase enzyme activity in cultured skin fibroblasts or
lymphoblastoid cells showing reduced activity (≤60%) or by molecular genetic
testing. The FH gene (1q42.1) is the only gene known to be associated
with HLRCC. Between 80% and 100% of individuals with HLRCC have identifiable
sequence variants in FH. No correlation is observed between FHmutations and the occurrence of cutaneous lesions, uterine fibroids, or renal
cancer of HLRCC. The proportion of cases caused by de novo mutations is
unknown as subtle manifestation in parents has not been evaluated and genetic
testing data are insufficient. Early detection of at-risk individuals affects
medical management. In the absence of an increased risk of developing childhood
malignancy, however, the American Society of Clinical Oncology (ASCO) recommends
delaying genetic testing in at-risk individuals during childhood until
individuals reach 18 years of age and are able to make informed decisions
regarding genetic testing.

Mutations
in the FH gene also occur in the
autosomal recessive condition fumerase deficiency (FHD), or fumeric aciduria.
FHD results from inherited biallelic mutations in FH, and is
characterized by rapidly progressive neurologic impairment including hypotonia,
seizures, and cerebral atrophy. Homozygous or compound heterozygous germline
mutations in FH are found in individuals with FHD. Leiomyomas and renal
cancer have not been reported in FHD. Most individuals with FHD, however,
survive only a few months; a very few survive to early adulthood. In one
report, a parent (heterozygous carrier) of an individual with fumarase
deficiency developed cutaneous leiomyomas similar to those observed in HLRCC.

Genes (1)

Indications

Confirmation of a clinical diagnosis of HLRCC in individuals who have tested negative for sequence analysis

Individuals at-risk for HLRCC due to family history who have tested negative for sequence analysis

Methodology

DNA isolated from peripheral blood is hybridized to a CGH array to detect deletions and duplications. The targeted CGH array has overlapping probes which cover the entire genomic region.

Please note that a "backbone" of probes across the entire genome are included on the array for analytical and quality control purposes. Rarely, off-target copy number variants causative of disease may be identified that may or may not be related to the patient's phenotype. Only known pathogenic off-target copy number variants will be reported. Off-target copy number variants of unknown clinical significance will not be reported.

Detection

Detection is limited to duplications and deletions. The CGH array will not detect point or intronic mutations. Results of molecular analysis must be interpreted in the context of the patient's clinical and/or biochemical phenotype.

Type: Whole Blood

Specimen Collection and Shipping: Refrigerate until time of shipment. Ship sample within 5 days of collection at room temperature with overnight delivery.

Type: Saliva

Specimen Requirements:

OrageneTM Saliva Collection kit (available through EGL) used according to manufacturer instructions.

Specimen Collection and Shipping: Store sample at room temperature. Ship sample within 5 days of collection at room temperature with overnight delivery.

Special Instructions

Submit copies of diagnostic biochemical test results with the sample, if appropriate. Contact the laboratory if further information is needed.

Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed outside of Emory Genetics Laboratory, please submit a copy of the sequencing report with the test requisition.

Related Tests

Sequencing analysis of the FH gene is available (VI) and is required before deletion/duplication analysis.

Prenatal
testing is available to individuals who are confirmed carriers of
mutations. Please contact the laboratory genetic counselor to discuss
appropriate testing prior to collecting a prenatal specimen.